Bi-allelic variants in the ESAM tight-junction gene cause a neurodevelopmental disorder associated with fetal intracranial hemorrhage.

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as "tightjunctionopathies."

Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.

BACKGROUND: Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis. METHODS: In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher's exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity. FINDINGS: Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7-10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22-67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS <2) and 17 (15%) moderate to severe deficits (mRS >2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05-0·59). INTERPRETATION: The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications. FUNDING: Mutua Madrileña Foundation; ISCIII-Subdirección General de Evaluación y Fomento de la Investigación Sanitaria; Fondo Europeo de Desarrollo Regional; Pediatrics Spanish Society; Departament de Salut, Generalitat de Catalunya; Marato TV3 Foundation; Red Española de Esclerosis Múltiple; La Caixa Foundation; and Fundació CELLEX.

Alimemazine poisoning as evidence of Munchausen syndrome by proxy: A pediatric case report.

Munchausen syndrome by proxy (MSBP), also known as fabricated or induced illness in a child by a caretaker, is a form of abuse where a caregiver deliberately produces or feigns illness in a person under his or her care, so that the proxy will receive medical care that gratifies the caregiver. The affected children are often hospitalized for long periods and endure repetitive, painful and expensive diagnostic attempts. We present an analytically confirmed case of MSBP by alimemazine. A 3-year-old boy was brought repetitively to a Pediatric Emergency Department by his mother because he presented limb tremors, dysarthria, obnubilation, and ataxia and generalized tonic-clonic seizures coinciding with intermittent fever. Neither the rest of the physical examination nor the complementary tests showed any significant alterations. MSBP was suspected and a routine systematic toxicological analysis in urine and blood was requested. Alimemazine was detected in all biological samples. The administration of this drug was never mentioned by the mother and the subsequent interview with her corroborated the suspicion of MSBP. Clinically, after separation from the mother, the child's neurological symptoms gradually improved until the complete disappearance of the cerebellar symptoms. Alimemazine was quantified in serum, urine, gastric content and cerebrospinal fluid samples by gas chromatography-mass spectrometry (maximum serum level was 0.42µg/ml). Hair quantification of alimemazine was performed by ultra-performance liquid chromatography-tandem mass spectrometry in different segments of hair. The results confirmed regular substance use during the at least eight last months (8.8, 14.7, 19.7 and 4.6ng/mg hair starting from most proximal segment). This patient represents the first case published with analytical data of alimemazine in blood, urine, gastric content, cerebrospinal fluid and hair, which allowed us to prove an acute and repetitive poisoning with alimemazine as evidence of MSBP.

Cervicothoracic extradural arachnoid cyst: possible association with obstetric brachial plexus palsy.

The association of cervicothoracic extradural arachnoid cysts and obstetric brachial plexus palsy has not previously been reported. We report two patients with this association. The first patient is a 9-month-old boy with left obstetric brachial plexus palsy that developed bilateral leg weakness at 6 months of age owing to compression of the spinal cord by a C6 to T8 left cervicothoracic extradural arachnoid cyst. The second patient is a 3-year-old girl with bilateral brachial plexus palsy and spastic paraparesis who had magnetic resonance imaging at 3 days of age that showed intraspinal cord injury and a cervicothoracic extradural arachnoid cyst compressing the spinal cord. We believe that the association of cervicothoracic epidural arachnoid cysts and obstetric brachial plexus palsy in these patients was causal and recommend that the possibility of a cervicothoracic epidural arachnoid cyst be considered in patients with brachial plexus palsy and evidence of spinal cord injury.

Paroxysmal non-kinesigenic dyskinesia due to a PNKD recurrent mutation: report of two Southern European families.

Paroxysmal non-kinesigenic dyskinesia (PNKD) is an autosomal dominant disorder characterized by attacks of dystonic or choreathetotic movements precipitated by stress, fatigue, coffee, alcohol or menstruation. In this report we present two families with PNKD of Southern European origin carrying a PNKD recurrent mutation. Incomplete penetrance and intrafamilial variability was detected in both families. Treatment with valproic acid and levetiracetam provided favorable response.

Clinical and radiological features of childhood cerebral infarction following varicella zoster virus infection.

The aim of the study was to describe the clinical and radiological features of childhood post-varicella cerebral infarction (PVCI). A retrospective review was undertaken of children with arterial ischaemic stroke (AIS) who had experienced varicella zoster virus (VZV) infection within the preceding year. Twenty-four children (15 males, nine females; age range at time of VZV infection 2mo-6y) were identified, with a median of 4 months between VZV and AIS (range 1wk-12mo). All had infarction in the middle cerebral artery (MCA) territory and abnormalities of the M1 segment; arteriopathy affected other arteries in 10 children. After a median of 27 months, six patients had recurrent transient ischaemic attacks (TIA), with new infarcts in two of 22 children on re-imaging. Arterial disease improved in 11 children, was stable in four, and progressed in seven (of whom four had recurrent TIA and two had re-infarction). PVCI affects young, previously healthy children within a few months of VZV infection and is characterized by MCA territory infarction and proximal MCA disease. One quarter of patients have recurrence, usually, but not inevitably, associated with progressive arteriopathy. Treatable co-existing AIS risk factors should always be excluded. A more comprehensive diagnostic evaluation should be considered in children with AIS who do not fit the clinical and radiological profile outlined, even where there is a history of recent VZV infection.

Post-varicella intracranial haemorrhage in a child.

We report a case of a 7-month-old male with primary intracranial haemorrhage 2 months after infection with varicella zoster virus (VZV). His initial clinical course was complicated by seizures and right hemiparesis; when last seen at 22 months the only positive finding was of left hand preference. Although the literature has recently established the association of arterial ischaemic stroke and VZV infection, primary intracranial haemorrhage has been reported only in one case. The child reported here had anterior interhemispheric haemorrhage due to a focal arteritis of the left anterior cerebral artery. The vascular abnormality was transient and had radiological features compatible with either a focal arteritis or vasospasm as a direct result of blood surrounding the vessels. We postulate that direct invasion of VZV caused extensive inflammation of the vessel wall and aggressive tissue penetration resulting in necrotizing angiitis and intracranial haemorrhage. We suggest that VZV infection should be considered a potential risk factor for intracranial haemorrhage in children.

Methemoglobinemia in an infant receiving nitric oxide after the use of eutectic mixture of local anesthetic.

High levels of methemoglobinemia can cause tissue hypoxia and cyanosis. We report the case of a 7-month-old girl with pulmonary dysplasia receiving inhaled nitric oxide who had cyanosis caused by methemoglobinemia after prolonged use of a eutectic mixture of local anesthetics cream.